Process for producing fast-setting, bioresorbable calcium...

Details Process for producing fast-setting, bioresorbable calcium... Process for producing fast-setting, bioresorbable calcium...

1999-07-14

2002-04-30

Langel, Wayne (Department: 1754)

Compositions: coating or plastic

Coating or plastic compositions

Inorganic settable ingredient containing

C106S035000, C106S691000

Reexamination Certificate

active

06379453

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for producing fast-setting, bioresorbable calcium phosphate cements (CPC), and in particular, to a process including a pre-heat treatment step to generate uniformly distributed submicron-sized apatite seeds.
DESCRIPTION OF THE RELATED ART
Due to its superior biocompatibility and osteoconductivity, CPC has been used as implant or filling material in dental or bone prosthesis and the like (Chow et al., 1991;Chohayeb et al., 1987: Costantine et al., 1991j; Firedman et al; Hong et al; 1991; Sugawara et al., 1992; Hamanish et al; 1996). In 1983, Brown and Chow indicated that mixing tetracalcium phosphate (TTCP) and dicalcium phosphate anhydrous (monetite) (DCPA) powder to obtain a powder mixture and mixing the powder mixture in a diluted phosphate-containing solution can obtain hydroxyapatite (HA). Implants made from thus produced HA have a compressive strength up to 51 MPa. However, in application, the setting time is too long (for example, 30 minutes) and the mechanical properties are still inferior compared to enamel, tooth and metal composite. Moreover, as the setting time is long, the material can be flushed away by body fluid/blood before it is set.
A great deal of effort has been expended to solve the long setting time problems. U.S. Pat. No. 4,959,104 provides a process for producing a fast-setting CPC which becomes set within several minutes. Inorganic fluorides, such as CaF
2
, MgF
2
and BeF
2
are added to increase the compressive strength of the CPC. NaF, LiF or KF is added in the organic acid or inorganic acid solution to shorten the setting time to form a stable apatite type product.
U.S. Pat. No. 5,092,888 provides a hardening material comprising (1) a powder component composed of a powdery mixture of tetracalcium phosphate and calcium phosphate having a Ca/P atomic ratio lower than 1.67 and (2) a liquid component composed of a colloidal aqueous solution comprising solid colloid particles dispersed in an aqueous medium.
U.S. Pat. No. 5,180,426 provides a calcium phosphate type setting material comprising (1) powder comprising at least one of &agr;-tricalcium phosphate and tetracalcium phosphate; and (2) a setting solution comprising an aqueous acidic solution having dissolved therein at least one polysaccharide selected from the group consisting of carboxymethyl chitin, glycol chitin, pullalan, high methoxy-pectin and chitosan.
U.S. Pat. No. 5,262,166 provides a surgical cement comprising a calcium alkali phosphate cement with relatively high surface pH of about 7 or higher. In the calcium alkali phosphate cement, citric acid, acidic citrate salts are added as setting agent and CaO, Na
2
O, P
2
O
5
, MgO and collagen are added to shorten the setting time.
U.S. Pat. Nos. 5,336,264 and 5,820,632 show that setting times of calcium phosphate cement compositions are enhanced by the addition of sodium phosphate or sodium carbonate lubricant compositions.
U.S. Pat. No. 5,525,148 provides a composition relating to calcium phosphate cement that self-hardens substantially to hydroxyapatite at ambient temperature when in contact with an aqueous medium. Phosphates such as Na
3
PO
4
, Na
2
HPO
4
and NaH
2
PO
4
are added in the composition.
As discussed above, these approaches use metal ion-containing compounds, polymeric compounds or collagens as the setting agents to improve the long setting time problem. Metal ions in setting agents may cause diseases when applied in vivo. Some evidence shows that aluminum ions might be associated with peripheral neuropathy, osteomalacia and aizheimer diseases; vanadium ions can cause cytotoxicity; Ni and Cr compounds may cause cancer; and Ni or Cr metal ions can induce the immunological sensitization of human beings. Although titanium and titanium alloys are considered bio-compatible, it was recently reported that scraps of titanium alloys may also cause detrimental reactions to the vicinal living tissues or cause cytotoxicity (K. Soballe, “Hydroxyapatite ceramic coating for bone implant fixation”, ACTA Orthopaed. Scandin Supplem., 64:1-58, 1993; J. J. Callaghan, Current concerts review, “The clinical results and basic science of total hip arthroplasty with porous-coated prostheres” J. Bone Joint Surg., 75A: 299-310, 1993). Polymeric compounds may degrade into their monomers which are also detrimental biologically. While collagens are biocompatible, their dissolution rates are usually too high and found practically inconvenient.
Bioresorbable materials have advantages when being used in medical implants. Bioresorbable materials will be gradually degraded when they are implanted in animals or humans, thus allowing replacement by new bone growth.
U.S. Pat. No. 5,053,212 discloses the production of a bioresorbable hydroxyapatite. A dry mixture is first provided in which TTCP and ortho-phosphoric crystals, monocalcium phosphate monohydrate are combined with mechanical mixing to control the Ca/P ratio to approximately 1.25-2.0:1. The dry mixture is then mixed with water or polyols or ethylene glycol to obtain the bioresorbable hydroxyapatite.
U.S. Pat. No. 5,149,368 provides a process for the preparation of bioresorbable calcium phosphate cement. The process uses decomposable tricalcium phosphate and tetracalcuim phosphate as main ingredients and undecomposable hydroxyapatite as secondary ingredients. These ingredients are intensively mixed with setting agents, i.e., acidic citrate, to obtain a mixture and the mixture is then mixed with an appropriate solvent to obtain a slurry. NaOH, KOH or NH
4
OH is added to adjust the pH to greater than 5. Antibiotics and bone morphological proteins are also added. The resultant calcium phosphate cements are biocompatible, bioresorbable and have satisfactory working time.
U.S. Pat. No. 5,342,441 provides a biocompatible composition which includes a powder component containing Ca
4
P
2
O
9
and at least one of CaHPO
4
and CaHPO
4
H
2
O at a molar ratio of Ca:P of 1.16-1.95; and a liquid component containing 1 mM to 2M of a second phosphate ion and 1 mM to 2M of an organic ion. The biocompatible material converts into hydroxyapatite when being implanted into human or animals and a part thereof can be replaced by newly grown bones.
U.S. Pat. No. 5,503,164 provides a method for the repair of craniomaxillofacial bony defects using a low temperature-hardening, gradually resorbable hydroxyapatite forming cement. The resorbable hydroxyapatite forming cement is obtained by adding some bio-dissolvable salts such as silicate acrylic salts.
U.S. Pat. Nos. 5,542,973, 5,545,254 and 5,695,729 provide a composition comprising tetracalcium phosphate which has been prepared from a mixture with a calcium to phosphorous ratio of less than 2 under substantially anhydrous or vacuum conditions and which is converted substantially to hydroxyapatite upon setting.
U.S. Pat. No. 5,814,681 provides a restorative composition for hard tissue, comprising a paste (A) containing an inorganic calcium phosphate powder, a polymerizable monomer mixture and a polymerization initiator, and a paste (B) containing an inorganic calcium phosphate powder, a polymerizable monomer mixture and a polymerization accelerator.
However, these processes for producing biodegradable compositions use expensive additives or require a complicated procedure, such as being conducted in a vacuum or a water-free ambient.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide simple, inexpensive and easy to control process for producing a fast-setting biocompatible, bioresorbable calcium phosphate cement.
The invention accomplishes the above object by providing a process comprising the following steps: obtaining a powder mixture from at least one calcium phosphate selected from the group consisting of Ca
4
(PO
4
)
2
O, CaHPO
4
2H
2
O, CaHPO
4
, Ca
8
H
2
(PO
4
)
6
5H
2
O, &agr;-Ca
3
(PO
4
)
2
, &bgr;-Ca
3
(PO
4
)
2
, Ca
2
P
2
O
7
, Ca
2
H
2
P
2
O
8
, wherein the molar ratio of Ca to P in the mixture is roughly between 1 and 2; mixing the powder mixture in a phosphate-containing

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